In order to investigate the improvement of insulin resistance and cardiac autonomic function along massive weight loss, 12 obese women were evaluated before, and 3 and 12 months after Roux-en-Y gastric bypass. The 12-month values were compared to those of BMI-matched controls. Insulin sensitivity was assessed by euglycemic clamp and the cardiac autonomic function by the analysis of the Heart Rate Variability (HRV). After surgery, glucose uptake progressively increased from 4.3 +/- 0.5 mg/kg lean body mass (LBM)/min preoperative (pre-op) to 4.9 +/- 0.5 and 7.0 +/- 0.5, 3- and 12-month postoperative (post-op) (P = 0.04 and P = 0.006 vs. pre-op), whereas the cardiac autonomic function showed a biphasic pattern. HRV values increased 3 months post-op, and decreased at 12 months, thus indicating an early sympathetic withdrawal followed by a later reactivation (e.g., the standard deviation of the normal-to-normal intervals was 116 +/- 7 ms in pre-op, 161 +/- 10 at 3 months, P = 0.008 vs. pre-op, and 146 +/- 15 at 12 months, P = 0.03 vs. pre-op and P = 0.02 vs. 3 m). Insulin sensitivity was significantly related to body weight (P = 0.02), whereas the cardiac indexes were significantly linked to the profile of energy intake (e.g., HRV triangular index vs. energy intake P = 0.003). No significant relationship linked insulin sensitivity to the cardiac autonomic indexes. Insulin sensitivity and cardiac parameters of the 12-month post-op patients were similar to their matched controls. During massive weight loss, the cardiac autonomic deregulation and insulin resistance improved concomitantly but independently from each other. Our results suggest that the extent of the improvement is associated with the final body weight.